Cited by 128Protein Structure and DynamicsEnzyme Structure and FunctionAdvanced NMR Techniques and Applications

Finding Our Way in the Dark Proteome

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Bhowmick, Asmit, Brookes, David H., Yost, Shane R., Dyson, H. Jane, Forman-Kay, Julie D., Gunter, Daniel, Head-Gordon, Martin, Hura, Gregory L. +4 more·2016·Journal of the American Chemical Society

Abstract

The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines. However, approximately one-third of the human proteome is comprised of intrinsically disordered proteins and regions (IDPs/IDRs) that do not adopt a dominant well-folded structure, and therefore remain "unseen" by traditional structural biology methods. This Perspective considers the challenges raised by the "Dark Proteome", in which determining the diverse conformational substates of IDPs in their free states, in encounter complexes of bound states, and in complexes retaining significant disorder requires an unprecedented level of integration of multiple and complementary solution-based experiments that are analyzed with state-of-the art molecular simulation, Bayesian probabilistic models, and high-throughput computation. We envision how these diverse experimental and computational tools can work together through formation of a "computational beamline" that will allow key functional features to be identified in IDP structural ensembles.

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  1. [1]Dunker AK Lawson JD Brown CJ Williams RM Romero P Oh JS Oldfield CJ Campen AM Ratliff CM Hipps KW Ausio J Nissen MS Reeves R Kang C Kissinger CR Bailey RW Griswold MD Chiu W Garner EC Obradovic Z J Mol Graph Model 2001 19 26 11381529
  2. [148]Sugita Y Okamoto Y Chemical Physics Letters 1999 314 141

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Authors
Bhowmick, A., Brookes, D. H., Yost, S. R., Dyson, H. J., Forman-Kay, J. D., Gunter, D., Head-Gordon, M., Hura, G. L., Pande, V. S., Wemmer, D. E., Wright, P. E., & Head-Gordon, T.
Affiliations
  • University of California, Berkeley (US)
  • Scripps Research Institute (US)
  • University of Toronto (CA)
  • Stanford University (US)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
  • Forman-Kay, Julie D.
  • Head-Gordon, Teresa
Venue
Journal of the American Chemical Society
Published
2016-07-19
Volume
138
Issue
31
Pages
9730-9742
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
OpenAlex
W2470406062
Cited by
128
References
176
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 15 · 2020: 14 · 2019: 26 · 2018: 23 · 2017: 20 · 2016: 1
FWCI
12.13
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Division of Chemistry (CHE-1363320)
  • National Cancer Institute (CA96865)
  • Canada Research Chairs
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-06718)
  • National Institute of General Medical Sciences (GM113251)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
Keywords
intrinsically disordered proteins, intrinsically disordered regions, dark proteome, protein conformational ensembles, solution structure determination, Bayesian probabilistic model, molecular simulation, protein function
MeSH terms
Bayes Theorem, Chromatography, Gel, Humans, Kinetics, Magnetic Resonance Spectroscopy, Probability, Protein Conformation, Software, Genome, Human, Protein Folding, Crystallography, X-Ray, Computational Biology, Proteome, Proteomics, Molecular Dynamics Simulation, Intrinsically Disordered Proteins

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